Recently, the prevalence of gout has increased each year, and the age of onset has shown a trend towards a younger age due to an improvement the standard of living.
Men and menopausal women are vulnerable to gout, and the peak incidence is 40-50 years old. The clinical features of gout are hyperuricemia, recurrence of gouty acute arthritis, deposition of gouty tophus, characteristic chronic arthritis and joint deformity. The kidney is generally involved, causing chronic interstitial nephritis and uratic nephrolithiasis. The prerequisite of gout is hyperuricemia, i.e. the saturated concentration of uric acid in serum at 37° C. is about 420 μmol/L (70 mg/L). One is suffering from hyperuricemia when the concentration of uric acid in serum is higher than the above-mentioned value. However, only some hyperuricemia patients develop gout, and its mechanism is unclear. Only hyperuricemia patients with deposition of urate crystal, arthritis and/or kidney disease, kidney stone etc. are considered to suffer from gout. Therefore, hyperuricemia is an important biochemical basis index of gout, and is closely related to the onset of gout. Hyperuricemia is closely related to the onset of hypertension, hyperlipidemia, atherosclerosis, obesity and insulin resistance, and has become a serious metabolic disease that threatens human health.
Uric acid is the final product of purine metabolism in humans. Uricase is absent due to genetic mutation of uricase during human evolution, and uric acid thus cannot be metabolized into soluble allantoin for removal from the body. Therefore, there is an excess of serum uric acid concentration in hyperuricemia patients. The onset of hyperuricemia is due to: (1) increased uric acid production, which accounts for 15% to 20% of gout onset, for example, diets enriched with purine are consumed in excess, or more uric acid is synthesized from amino acids and nucleotides in vivo, and excessive uric acid is produced from the catabolism of nucleic acids; and (2) decreased uric acid excretion and increased uric acid reabsorption, which are the main pathogenesis of hyperuricemia and gout, account for about 80% to 85% of gout onset. About 95% of uric acid reabsorption is performed by Uric Acid Transporter 1 (URAT1) located in the epithelial cells of the renal proximal tubule. URAT1 is a complete membrane protein located in the kidney, which belongs to the solute carrier 22 (SLC22) family. It performs urate-anion exchange, and is responsible for the regulation of uric acid levels in the blood. Therefore, URAT1 inhibitors could enhance the excretion of uric acid by inhibiting such reabsorption.
There are very few anti-gout drugs on the pharmaceutical market in China. Allopurinol and benzbromarone are still the main drugs, and no novel and better anti-gout drug has been developed. Febuxostat, approved by the FDA in 2009, is a xanthine oxidase (XO) inhibitor. It treats gout by reducing the production of uric acid. RDEA-594 (Lesinurad), developed by Ardea Biosciences Inc., enhances the excretion of uric acid by inhibiting Uric Acid Transporter 1 (URAT1), thereby achieving the purpose of reducing the serum concentration of uric acid. Its efficacy is not affected by renal function and the dosage of allopurinol. It does not alter the transport effect of Organic Anion Transporter 1/3 (OAT1/OAT3) within clinical dosage. In addition, it is more specific for its targets as compared with other uricosuric drugs, and has less interactions with other drugs.
